Department of Orthopedics, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, PR China; Department of Orthopedics, Fujian Pingtan Comprehensive Experimental Area Hospital, Fuzhou 350400, Fujian Province, PR China.
Department of Orthopedics, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, PR China.
Bone. 2024 Nov;188:117222. doi: 10.1016/j.bone.2024.117222. Epub 2024 Aug 3.
Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research.
SANFH models both in vivo and in vitro were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays.
Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy in vitro, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats.
ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment.
唑来膦酸（zoledronic acid，ZOL）是一种双膦酸盐，对骨科疾病具有良好的治疗效果。然而，ZOL 对激素诱导性股骨头坏死（steroid-induced avascular necrosis of femoral head，SANFH）的药理作用及其潜在机制尚不清楚，值得进一步研究。
通过地塞米松（dexamethasone，Dex）刺激建立体内和体外 SANFH 模型。通过 TRAP 染色检测破骨细胞生成。免疫荧光法检测自噬标志物（LC3）水平。TUNEL 染色分析细胞凋亡。采用 ChIP 和双荧光素酶报告基因检测分析 Foxhead box D3 蛋白（FOXD3）与 Annexin A2（ANXA2）启动子之间的相互作用。
Dex 加重体外破骨细胞生成，并诱导破骨细胞分化和自噬，而 ZOL 处理可阻断这一过程。PI3K 抑制剂 LY294002 消除了 ZOL 对 Dex 诱导的破骨细胞分化和自噬的抑制作用。FOXD3 过表达通过转录激活 ANXA2 中和了 ZOL 对 Dex 诱导的破骨细胞的下调作用。ANXA2 敲低逆转了 FOXD3 过表达对 ZOL 介导的 Dex 处理破骨细胞中生物学效应的影响。此外，ZOL 改善了大鼠的 SANFH 症状。
ZOL 通过调节 FOXD3 介导的 ANXA2 转录活性，进而促进 PI3K/AKT/mTOR 通路，减轻 SANFH，表明 FOXD3 可能是 ZOL 治疗 SANFH 的靶点。
